The purpose of this application is to seek renewed funding for a long-running prospective cohort of HIV- infected individuals who use injection drugs (IDU) linked to comprehensive HIV clinical monitoring to examine the impacts of individual, social, policy, economic, and physical exposures on HIV treatment outcomes. We seek to analyse the effects of these contextual determinants, including incarceration, homelessness, and involvement in the sex trade, on HIV RNA plasma viral load at both the individual and community levels. We will augment our ongoing epidemiologic and clinical research activities with molecular genetics and geographic information systems (GIS) based methods to model the effect of these exposures on community-level plasma viral load, HIV incidence, and the generation of antiretroviral drug resistance. In recognition of the increasing international attention to the HIV risk environment, a conceptual framework modeling the effect of exogenous and endogenous characteristics on the risk of HIV infection, we will employ this structure to integrate data from individual and community levels in analyses of HIV treatment outcomes. This proposal comes at a time of broad international consensus on the need to respond urgently to persistently elevated levels of HIV-related morbidity and mortality among IDU. Emerging evidence from mathematical modeling, observational cohorts and clinical trials has revealed the close link between the HIV RNA viral load within individuals and at the community level and the risk of HIV transmission between individuals, resulting in lower rates of infection in populations with higher levels of coverage of highly active antiretroviral therapy (HAART.) This observation has led to renewed HIV prevention efforts to seek out members of vulnerable populations, test them for HIV infection, and engage them in healthcare, including treatment for HIV infection, in order to reduce HIV-related morbidity and mortality and lower the incidence of HIV seroconversion. Our proposed study will be conducted during a province-wide Seek, Test, and Treat campaign. Given the study infrastructure established to date and our track record evaluating barriers to HAART access and adherence, we are uniquely well placed to prospectively assess second-generation questions regarding the treatment as prevention campaign's impacts on community-level plasma viral loads, HAART resistance, and HIV incidence. In this regard, evaluations of treatment as prevention are an urgent priority in the FY 2012 Trans-NIH Plan for HIV-Related Research. In addition to the Seek, Test, and Treat campaign, our study setting of Vancouver, Canada, is ideally suited to our study aims. The universal healthcare system provides all medical care, including HAART, free of charge. Confidential record linkages allow the accurate attainment of all key measures, including health service utilization and HIV clinical outcomes. This application proposes a program of rigorous and innovative study that will marshal epidemiologic, geographic, and phylogenetic approaches to critically inform efforts to respond to HIV transmission and pathogenesis among IDU. PUBLIC HEALTH RELEVANCE: High levels of HIV infection among people who use injection drugs is a global public health emergency. In response, we propose to renew our ongoing study of HIV-positive drug users to assess the effect of HIV treatment on patterns of antiretroviral drug resistance and patterns of HIV transmission in Vancouver, Canada.